Semaglutide & Weight Management–Safety & Effectiveness
Young Ju, Ph.D.
Those who regularly play tennis may not struggle with weight issues as much as people who are sedentary. Yet it is a subject of interest and concern for many of us. You may know friends or family who meet specific criteria and have been taking Ozempic® or Wegovy® to manage body weight. These are brand names for a recent generation of anti-obesity medication containing semaglutide. If you are considering this alternative, it is important to know how these drugs work, how safe they are, and what are the potential side effects of long-term use.
Obesity
Obesity is defined as “abnormal or excessive fat accumulation that might impair health.” (1) It is the primary health condition that increases the risk of many chronic diseases, including hypertension, type 2 diabetes, cardiovascular disease, chronic kidney disease, fatty liver disease, sleep disorders, osteoarthritis, and certain cancers.
The prevalence of obesity in American adults was about 40.3% during 2021-2023 (2) with the highest in ages 40-59. The prevalence of severe obesity was 9.4% (increasing from 7.7% during 2013-2014); severe obesity is higher in women.
A body mass index (BMI) is one convenient (but not perfect) indicator used to define your body weight category. BMI should not be the only method used to estimate fat mass as it is a simple calculation of weight divided by height.
Semaglutide (3,4,5)
The FDA approved the use of semaglutide, a modern class of medications for type 2 diabetes, under the brand name Ozempic® (0.25-1 mg, once-weekly injection) in Dec 2017. In 2020, the FDA expanded its uses to include reducing the risk of cardiovascular events (a group of conditions that affect the heart and blood vessels) in adults with type 2 diabetes and heart disease. Ozempic® has been also used as off-label medication to treat overweight and obese–off-label refers to using a medication in a way different from what the FDA has approved.
In 2021, the FDA approved a higher-dose version of semaglutide, Wegovy® (2.4 mg), for long-term weight management in adults.
Since 2022, semaglutide products have been on the FDA’s shortage list due to their fast-growing popularity. In Jan 2025, the FDA approved semaglutide for chronic kidney disease. In Feb 2025, the FDA announced that the shortage of semaglutide injection products had been resolved.
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist which mimics the effects of GLP-1, a hormone called incretin which is released from the small intestine after eating. GLP-1 receptors are widely found throughout the body, including in the gastrointestinal tract (stomach, small intestine, and large intestine), the pancreas, the liver, the kidneys, and in the areas of the brain that regulate digestion, appetite, and glucose metabolism.
When it binds to a receptor, GLP-1
triggers the release of insulin from the pancreas and reduces the release of glucagon (a hormone that counteracts insulin) from the pancreas (6)
helps uptake glucose from the blood into cells, lowering blood glucose levels (6)
reduces glycogen (stored energy source) breakdown to glucose in the liver, improving glucose metabolism and reducing fatty liver (7)
binds to GLP-1 receptors in the hypothalamus of the brain, reducing hunger and food cravings, and slowing gastric emptying
exerts kidney protective effects, improving kidney function and reducing protein loss (8)
A GLP-1 receptor agonist is recommended as a second or third-line treatment for type 2 diabetes when oral anti-diabetic medication (e.g., metformin) and other initial anti-diabetic treatments are not sufficient, not effective, not tolerated, or for people with a BMI of ≥30, or in people with a BMI of <27 for whom insulin treatment would be unsuitable, either occupationally or in worsening obesity-related comorbidities (9, 10, 11).
Anti-Obesity Treatments (11, 12, 13)
In general, obesity treatments can fall into three major categories:
lifestyle interventions (diet, physical activity, behavioral strategies)
pharmacotherapy (anti-obesity medications)
bariatric procedures
Anti-obesity medications can be used in combination with lifestyle interventions for people with BMI ≥30 or people with BMI ≥27 and at least one weight-related health condition (e.g., type 2 diabetes, cardiovascular disease, and osteoarthritis). Several classes of anti-obesity medications are approved by the US FDA for long-term weight management. A healthcare provider will recommend a reduced-calorie diet and exercise while taking these medications.
These medications might be taken in the form of pills or daily or weekly injections. Some of the other anti-obesity drugs include orlistat, phentermine, naltrexone-bupropion, liraglutide, and tirzepatide.
Effectiveness of Semaglutide
One review (12) reported that semaglutide (2.4 mg) reduced body weight by 10-12% more at 12 months compared to the lifestyle-change-only group–which was more effective than groups taking other classes of anti-obesity medications, phentermine, naltrexone-bupropion, and liraglutide by 5-9% and phentermine-topiramate by 7-9%.
The study further showed that in people with type 2 diabetes and obesity, liraglutide lowered glycated hemoglobin (HbA1c) levels by 1.3% over 56 weeks, and semaglutide (2.4 mg) lowered it by 1.6% over 68 weeks.
Another recent review (13) concluded that GLP-1 receptor agonists reduced body weight by 7.4%-24.2%.
These studies have also found that users regain the weight when they stop taking semaglutide.
Side Effects and Safety (12, 13)
Side effects vary, but common ones include: nausea, vomiting, diarrhea, constipation, indigestion, abdominal pain, and headache like those of orlistat (an early generation anti-obesity medication). GLP-1 receptor agonists-induced side effects tend to lessen over time. Phentermine with or without topiramate and naltrexone-bupropion are associated with neuropsychiatric effects such as irritability and insomnia.
All anti-obesity medication classes except orlistat are associated with improved quality of life compared to lifestyle interventions alone.
Semaglutide is not recommended for people who have/are (4,11):
Digestive problems: It can worsen gastrointestinal issues.
Kidney disease: Semaglutide is primarily eliminated by the kidneys. In people with kidney disease, proper elimination could be impaired, leading to an accumulation of the drug.
Pancreatitis: It can stimulate the pancreas, worsening inflammation.
Medullary thyroid cancer: Animal studies have shown that semaglutide increases the risk of developing these cancer types.
Pregnant or breastfeeding: there are insufficient data on its safety.
Compounded Semaglutide
Compound drugs are copies of FDA-approved medications. They are made by licensed pharmacies but not approved by the FDA. A compounded drug might be appropriate when an FDA-approved drug is on the FDA’s shortage list or when a patient cannot take the FDA-approved drug or is not covered by health insurance. Warning: compounded drugs are often associated with dosing error and adverse effects.
Conclusion
Obesity is a complex multifactorial condition affecting numerous chronic diseases. Lifestyle interventions should still be the first-line method of managing healthy body weight. However, when lifestyle interventions alone are insufficient or ineffective, drug treatments are available in combination with lifestyle interventions. Research studies indicate that semaglutide products may be more effective in reducing body weight compared to other classes of anti-obesity medications. However, effectiveness and side effects of long-term use of these medications still need to be monitored. Drug makers are exploring various combinations of hormones and receptor agonists to enhance weight loss and improve tolerability.
For many individuals with obesity or weight management issues, this class of drugs can provide quality-of-life-changing results. As always, it is important to self educate and discuss your concerns with weight-related health conditions with your medical professional.
Dr. Young Ju is a Ph.D and Associate Professor of Human Nutrition, Foods, and Exercise at Virginia Tech.
References
World Health Organization. “Obesity” https://www.who.int/health-topics/obesity#tab=tab_1
The Center for Disease Control and Prevention National Center for Health Statistics. “Obesity and severe obesity prevalence in adults: United States, August 2021-August 2023” https://www.cdc.gov/nchs/products/databriefs/db508.htm#:~:text=The%20prevalence%20of%20obesity%20among,or%20in%20any%20age%20group.
U.S. Food & Drug Administration. “FDA approves new medication for chronic weight management.” https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
U.S. Food & Drug Administration. “FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss.” https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss
U.S. Food & Drug Administration. “FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize.” https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize
Mayendraraj et al. “GLP-1 and GLP receptor signaling in beta cells - A review of receptor interactions and co-stimulation” Peptides 2022, 151:170749.
Bu et al. “Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism” Diabetes & Metabolism Journal 2024, 48(3):354.
Tommerdahl et al. “Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonists” Advances in Chronic Kidney Disease 2021, 28(4):337.
Nauck et al. “GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art” Mol Metab. 2021, 46:101102.
Shields et al. “Patient stratification for determining optimal second and third line therapy for type 2 diabetes: the TriMaster study” Nat Med. 2023, 29(2):376.
National Institute of Diabetes and Digestive and Kidney Diseases. “Prescription Medications to Treat Overweight & Obesity” https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity
Perdomo et al. “Contemporary medical, device, and surgical therapies for obesity in adults. Therapeutics 2023, 401:1116.
Kokkorakis et al. “Emerging pharmacotherapies for obesity: A systematic review” Pharmacological Reviews 2025, 77(1):100002.
This information is provided for your reference and you use at your own risk; you should rely on your medical professional for medical advice.
